Fungal infections are responsible for a large portion of opportunistic infections in compromised hosts. Among the fungi, Candida albicans is one of the most prevalent agents causing secondary disease in patients weakened by cancer, immunosuppressive therapy, radiation treatment, and other debilitating conditions found in hospital-associated infections. The currently used anticandidal drugs suffer from significant clinical limitations. We propose to take advantage of the biochemical difference between the cell envelopes of Candida and mammalian tissue to design drugs specific for this pathogenic yeast. In particular, we will adapt the polyoxons for use against medically important fungi by smuggling them into the yeast cell via the peptide transport system. Since the polyoxins inhibit the synthesis of chitin, an essential cell wall structural macromolecule found in fungi and invertebrates but not in mammalian cells, such agents should be pathogen specific. At present various polyoxins strongly inhibit the in vitro activity of chitin synthetase from C. albicans but are not active in culture. The lack of in vivo activity can be traced to the low permeation by polyoxins into yeast. We will overcome this problem by synthesizing polyoxins either modified on their dipeptidyl moiety or containing an attached peptide carrier. Modification will be made in accordance with the structural requirements of the peptide transport system and in accordance with the structural requirements of the peptide transport system and structure-inhibition relationships of the polyoxins. Such modified antibiotics will be examined for their ability to inhibit chitin synthetase in vitro and to utilize the peptide transport system in C. albicans. The ability of potential drugs to inhibit growth of C. albicans in culture will be examined. Finally, successful candidates will be evaluated using model animal infections in mice.